The present invention provides immunoresponsive cells, including T cells, cytotoxic T cells, regulatory T cells, and Natural Killer (NK) cells, expressing an antigen recognizing receptor and an inhibitory chimeric antigen receptor (iCAR). Methods of using the immunoresponsive cell include those for the treatment of neoplasia and other pathologies where an increase in an antigen-specific immune response is desired.

Among the various aspects of the present disclosure is the provision of a chimeric antigen receptor memory-like (CARML) NK cell and methods of making and using same.

Described are improved methods for treating solid tumors, such as malignant gliomas, with a dual approach utilizing a CAR-T immunotherapy and a viral oncolytic therapy.

Described are improved methods for treating solid tumors, such as malignant gliomas, with a dual approach utilizing a CAR-T immunotherapy and a viral oncolytic therapy.

The present invention is directed to adenoviruses for use in cancer therapy which comprise one or more heterologous nucleic acid sequences encoding a tumor antigen, whereby the adenovirus expresses the tumor antigen(s) on its surface.

Methods for neutralizing and/or removing human GM-CSF in a subject in need thereof, comprising administering to the subject CAR-T cells having a GM-CSF gene knockout (GM-CSF.sup.k/o CAR-T cells) are provided. Also provided are methods for GM-CSF gene inactivation or GM-CSF knockout (KO) in a cell comprising targeted genome editing or GM-CSF gene silencing. Methods for preventing/treating immunotherapy-related toxicity, comprising administering to the subject CAR-T cells having a GM-CSF gene inactivation or GM-CSF knockout (GM-CSF.sup.k/o CAR-T cells), wherein the GM-CSF gene is inactivated or knocked out and/or a recombinant GM-CSF antagonist are provided. Methods for reducing a level of a cytokine or chemokine other than GM-CSF in a subject having immunotherapy-related toxicity comprising administering to the subject a recombinant hGM-CSF antagonist are provided. Also provided are methods for treating or preventing immunotherapy-related toxicity in a subject, comprising administering to the subject chimeric antigen receptor-expressing T-cells (CAR-T cells), the CAR-T cells having a GM-CSF gene knockout (GM-CSF.sup.k/o CAR-T cells). Methods for preventing or reducing blood-brain barrier disruption in a subject treated with immunotherapy, the method comprising administering CAR-T cells having a GM-CSF gene knockout (GM-CSF.sup.k/o CAR-T cells) to the subject, also are provided.

Methods for neutralizing and/or removing human GM-CSF in a subject in need thereof, comprising administering to the subject CAR-T cells having a GM-CSF gene knockout (GM-CSF.sup.k/o CAR-T cells) are provided. Also provided are methods for GM-CSF gene inactivation or GM-CSF knockout (KO) in a cell comprising targeted genome editing or GM-CSF gene silencing. Methods for preventing/treating immunotherapy-related toxicity, comprising administering to the subject CAR-T cells having a GM-CSF gene inactivation or GM-CSF knockout (GM-CSF.sup.k/o CAR-T cells), wherein the GM-CSF gene is inactivated or knocked out and/or a recombinant GM-CSF antagonist are provided. Methods for reducing a level of a cytokine or chemokine other than GM-CSF in a subject having immunotherapy-related toxicity comprising administering to the subject a recombinant hGM-CSF antagonist are provided. Also provided are methods for treating or preventing immunotherapy-related toxicity in a subject, comprising administering to the subject chimeric antigen receptor-expressing T-cells (CAR-T cells), the CAR-T cells having a GM-CSF gene knockout (GM-CSF.sup.k/o CAR-T cells). Methods for preventing or reducing blood-brain barrier disruption in a subject treated with immunotherapy, the method comprising administering CAR-T cells having a GM-CSF gene knockout (GM-CSF.sup.k/o CAR-T cells) to the subject, also are provided.

Provided herein are immunogenic compositions comprising a recombinant modified vaccinia virus Ankara (MVA) comprising a nucleic acid sequence encoding a CD40 ligand (CD4OL) and a nucleic acid sequence encoding a heterologous disease-associated antigen, wherein the immunogenic composition induces increases T-cell immune responses specific for the heterologous disease-associated antigen when administered to a human host, and related methods and uses.

The present invention relates to compositions comprising engineered allogenic immune cells endowed with Chimeric Antigen Receptors (CAR), in particular a CAR specific for CD123 and CLL1 for treating AML patients with adverse genetic risk.

Polypeptides are provided that bind CD123 on a target cell and the constant domain of TCR on a T cell. The polypeptides can be used in methods for treatment of CD123 associated cancers or inflammatory conditions.